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This pathway, centered around the molecule “mammalian
target of rapamycin (mTOR),” is known to play a paramount
role in the regulation of cell metabolism, growth and cell
division, as well as aging.

Neurodegenerative Conditions Damage Axons

Nerve cells talk to each other by transmitting electrical
signals along communication cables called axons, which are
enwrapped by insulating myelin sheaths. The myelin sheaths produced
by Schwann cells keep axons energized and healthy, and they
facilitate the propagation of electrical signals by a process known
as saltatory conduction.

“Myelin sheaths deteriorate in a number of
neurodegenerative conditions resulting in axon damage, most
prominently in peripheral neuropathies such as diabetic neuropathy
that is caused by metabolic tissue imbalances,” says lead and
corresponding author Bogdan
K. Beirowski, MD, PhD, assistant professor of biochemistry and
principal investigator at HJKRI. “The mTOR pathway is clearly
dysregulated in these conditions.”

“Diabetic neuropathy affects millions of people in the
United States and other developed countries due to our unhealthy
living conditions and fast food epidemic,” he adds.
“However, the mechanisms as to how mTOR perturbation may
affect myelin production are elusive.”

Learning Impact of Metabolic Abnormalities

A number of additional diseases are characterized by failed
formation of myelin sheaths during development, and researchers are
keenly interested in understanding why this happens. Earlier
studies suggested that mTOR may be one of the culprits as well.

Together, the implication of mTOR in myelination could provide
novel clues toward better understanding how metabolic abnormalities
can result in aberrant nerve structure and neurodegeneration.

As part of the study, the scientists showed that genetically
manipulated and sick Schwann cells with abnormally high levels of
mTOR activity are not able to form myelin sheaths in novel mutant
mice.

However, these Schwann cells can be healed and rejuvenated, even
after many months of malady in aged animals, by application of a
single mTOR inhibitor drug to form new and normal myelin sheaths,
Beirowski notes.

Research Aids Understanding of Nerve Regeneration

The findings from this preclinical study suggest that therapies
could be developed to counteract the withering away of myelin
sheaths in diseased nerves of patients.

“The study of our novel mouse mutants has uncovered
central details in the regulation of myelination by the mTOR
pathway in Schwann cells. The involvement of this pathway in
myelination has been proposed by other scientists, but our work in
Dr. Beirowski’s lab for the first time illustrates the
relevance of this fascinating molecule for overall Schwann cell
development,” says co-author Keit Men Wong, a doctoral student in
the neuroscience
program who performed a litany of biochemical and structural
analyses for the study.

“This discovery is also important for our understanding of
the biological mechanisms underlying nerve regeneration, in which
Schwann cells and their myelin sheaths play a pivotal role,”
says co-author Elisabetta Babetto, PhD, research assistant
professor in the HJKRI.

“However, much more research and hard work is needed to
know how exactly this pathway functions in Schwann cells and in
conjunction with neurons,” she adds. “Earlier studies
have also demonstrated the pathway is involved in neurons
itself.”

More Studies Aimed at Regenerating Myelin Sheaths

Beirowski is pursuing several follow-up studies resulting from
this collaborative work with Wong and Babetto.

“We are encouraged by our findings and think that our
discoveries could be exploited to regenerate myelin sheaths and
nerve structure to help patients with neurological
disorders,” he says.

The study was initiated in the laboratory of Jeffrey Milbrandt,
MD, PhD, of Washington University in St. Louis, who is co-author on
the paper.